Cardiovascular physiology


The main task of the heart is to supply the body with blood. This activity can be described by measurable parameters such as the heart rate, stroke volume, and cardiac output.

Basic definitions

During exercise, the SV and HR initially both increase to maintain a constant CO. As the HR continues to increase, SV at some point remains equal and then even gradually decreases due to decreased filling time in the very fast-beating heart. A constant CO is then only maintained by an increasing HR. As HR continues to rise above 160 bpm, CO starts decreasing as SV falls faster than HR increases. A healthy young adult can increase his or her CO about 4–5 times the resting rate.

Cardiac cycle

The cardiac cycle can be divided into two phases: the systole, in which blood is pumped from the heart, and the diastole, in which the heart fills with blood. Systole and diastole are each subdivided into two further phases, resulting in a total of four phases of heart action. Pressure and volume in the ventricles and atria change in a characteristic manner due to contraction and relaxation processes, with the pressure in the left ventricle changing the most and the pressure in the atria the least.


1.) Isovolumetric contraction

  • Main function: ventricular contraction
  • Occurs in early systole, directly after the atrioventricular valves (AV valves) close and before the semilunar valves open
  • All valves are closed
  • Ventricle contracts (i.e., pressure increases) with no corresponding ventricular volume change
    • LV pressure: 8 mm Hg∼ 80 mm Hg (when aortic and pulmonary valves open passively)
    • LV volume: remains ∼ 150 mL
  • The period of highest O2 consumption

2.) Systolic ejection

  • Main function: Blood is pumped from the ventricles into the circulation and lungs.
  • Follows isovolumetric contraction
  • Occurs during systole, between the opening and closing of the aortic valve
  • Ventricles contract (i.e., pressure increases) to eject blood, thereby decreasing the ventricular volume
    • Pressure: first increases from ∼ 80 mm Hg to 120 mm Hg and then decreases until aortic and pulmonary valves close
    • Volume: ejection of ∼ 90 mL SV (150 mL → 60 mL)


3.) Isovolumetric relaxation

  • Main function: ventricular relaxation
  • Follows systolic ejection
  • Occurs between aortic valve closing and mitral valve opening
  • All valves closed (volume remains constant)
  • The ventricle relaxes (i.e., pressure decreases) with no corresponding ventricular volume change until ventricular pressure is lower than atrial pressure and atrioventricular valves open
    • Pressure: decreases to ∼ 10 mm Hg
    • Volume: remains at ∼ 60 mm Hg

4.) Ventricular filling

  • Main function: ventricles fill with blood

Rapid filling

Reduced filling

  • Follows rapid filling
  • Occurs in late diastole; immediately before mitral valve closing
    • Pressure: ∼ 8 mmHg
    • Volume: ventricle fills with ∼ 90 mL (60 mL → 150 mL)

During isovolumetric contraction and relaxation, all heart valves are closed. There are no periods in which all heart valves are open!

Left ventricular pressure-volume diagram

  • Used to: measure cardiac performance
  • Shape: roughly rectangular; each loop is formed in an anti-clockwise direction
  • Course:
    • (1) End-diastolic state: left ventricle filled with blood
    • (1) → (2): Isovolumetric contraction with closed mitral and aortic valves
    • (2): Pressure becomes higher than the aortic pressure and the aortic valve opens → initiates ventricular ejection
    • (2) → (3): Volume and pressure decrease until pressure falls below aortic pressure and aortic valve closes
    • (3): End-systolic state
    • (4): Pressure falls, volume remains constant (isovolumic relaxation)
    • (4) → (1): Pressure falls below atrial pressure and mitral valve opens; the ventricle is filled with blood
    • (1): End-diastolic point; contraction begins

The width of the volume-pressure loop is the SV (the difference between EDV and ESV).

Heart excitation


  1. Pacemaker cells (e.g., sinus node) of the conduction system of the heart autonomously and spontaneously generate an action potential that spreads throughout the myocardium.
  2. The electrical excitation of the myocardium results in its contraction (electromechanical coupling).
  3. The phase of relaxation prevents immediate re-excitation (refractory period).

Conducting system of the heart

Cardiac channels

The action potentials of the pacemaker centers are transmitted to the cells of the myocardium via the cardiac conduction system, thereby depolarizing the cells (electromechanical coupling). As a result, voltage-activated calcium channels open, causing calcium ions to flow into the cardiomyocytes. Calcium binds to regulatory proteins of myofilaments (troponin) and allows interaction of actin and myosin. The muscle cell contracts. The exact course of the molecular interaction of actin and myosin (filament sliding theory) is dealt with in the basics of muscle tissue.

Calcium channels and calcium pumps

Name Definition Site

Direction of flow

Activation phase (affected tissue)

Calcium channels

Voltage-gated L-type calcium channel (iCa) Calcium channels on the surface of myocytes, which open at about -40 mV and allow intracellular calcium influx Cell membrane

Extracellular calcium → cytoplasm

Plateau phase (myocardium) and raising phase (SV node)
Ryanodine receptor

Calcium channel in the membrane of the sarcoplasmic reticulum that opens after binding of calcium (referred to as calcium-induced calcium release)

Membrane of SR

Ca2+ from SRcytoplasm

Plateau phase (myocardium)
Calcium pumps

SERCA (sarcoplasmic Ca2+-ATPase)

Calcium pumps and exchanger that remove calcium from the cytosol, thereby terminating a contraction

Membrane of SR

Ca2+ in cytoplasm→ sarcoplasmic reticulum

Plateau phase (myocardium)


Cell membrane Ca2+ in cytoplasm → extracellular

Other cation channels

All are located in the cell membrane.

Name Definition Ion and direction of flow Activation phase (affected tissue)
Funny channels (HCN, If) Nonselective cation channels (e.g., for Na+, K+) in pacemaker cells that open as the membrane potential becomes more negative (hyperpolarized) Cations extracellular → intracellular Raising phase (sinus node)

Fast sodium channels (INa)

Sodium channels that rapidly open and close following depolarization

Na+ extracellular → intracellular

Depolarization (myocardium)

Potassium channels

Inward rectifier K+ channels Potassium channels that open below −70 mV and stabilize the resting potential of the myocardiocytes by outflow of potassium K+ intracellular → extracellular Resting potential (myocardium > sinus node)
Delayed rectifier K+ channels(IKr & IKs)

Potassium channels that can be rapidly (IKr) or slowly (IKs) activated upon depolarization

K+ intracellular → extracellular Repolarization (sinus node and myocardium)

The long plateau phase from slow Ca2+ channels allows the myocardium to contract and pump blood effectively.

Cardiac action potential

Myocardial action potential (myocardium, bundle of His, Purkinje fibers) Pacemaker action potential (SA node and AV node)
Phase 0 (Upstroke and depolarization)
  • An action potential from a pacemaker cell or adjacent cardiomyocyte causes the transmembrane potential (TMP) to rise above −90 mV
  • Fast voltage-gated Na+ channels open at -65 mV → rapid Na+ influx into the cell TMP rises further until slightly above 0 mV (overshoot)
  • No external action potential needed (automaticity of SA and AV nodes = pacemaker cells can depolarize spontaneously)
  • No rapid depolarization phase because fast voltage-gated Na+ channels are inactivated in pacemaker cells → results in slower conduction velocity between atria and ventricles.
  • Gradual Na+/K+ entry via funny channels If (referred to as the funny current or pacemaker current) → slow spontaneous depolarization (TMP raises above -60 mV)
  • At TMP -40 mV (treshold potential of pacemaker cells): L-type Ca2+ channels open, TMP raises to +40 mV (overshoot)
Phase 1 (Early repolarization)
  • Voltage-gated Na+ channels close
  • Transient K+ channels start to open (outward flow of K+ returns TMP to 0 mV)
  • Absent
Phase 2 (Plateau phase)
  • Absent
Phase 3 (Repolarization)
  • Rapid repolarization due to:
    • Inactivation of voltage-gated Ca2+ channels
    • K+ efflux through delayed rectifier K+ channels continues: persistent outflow of K+ exceeds Ca2+ inflow and brings TMP back to -90 mV
  • The sarcolemmal Na+-Ca2+ exchanger, Ca2+-ATPase, and Na+-K+-ATPase restore normal transmembrane ionic concentration gradients (Na+ and Ca2+ ions return to extracellular space, K+ to intracellular space)
  • Closure of voltage-gated Ca2+ channels and
  • Opening of delayed rectifier K+ channels → K+ efflux (TMP returns to -60 mV)

Phase 4

(Resting phase)

  • Resting membrane potential stable at -90 mV due to a constant outward leak of K+ through inward rectifier channels
  • Na+ and Ca2+ channels closed

Pacemaker cells have no stable resting membrane potential. Their special hyperpolarization-activated cation channels (funny channels) ensure a spontaneous new depolarization at the end of each repolarization and are responsible for automaticity of the heart conduction system! In sympathetic stimulation, more If channels open, increasing the heart rate.

Upstroke and depolarization of a pacemaker cell are caused by the opening of voltage-activated L-type calcium channels. In other muscle cells and neurons, upstroke and depolarization are caused by fast sodium channels!

The duration of action potentials differs in the various structures of the conduction system and increases from the sinus node to the Purkinje fibers!

Refractory period

To ensure the proper length of time for chamber emptying (during systole) and refilling (during diastole) before the next contraction, and to prevent tetany of cardiac muscle, it is imperative that every contraction of the myocardium is followed by a sufficiently long period of relaxation. Therefore, a heart muscle cell is not re-excitable for a short time after depolarization, which is known as the refractory period. Due to the very long action potential of cardiomyocytes (200–400 ms), the first excited cardiomyocytes are still refractory while the last are still excited. On the one hand, this prevents circulatory excitations and, on the other hand, gives the cardiomyocytes enough time to contract and relax, without being disturbed by re-excitation!

The firing frequency of the SA node is faster than that of other pacemaker sites (e.g., the AV node. The SA node activates these sites before they can activate themselves (known as overdrive suppression).

The plateau phase of the myocardial action potential is longer than the actual contraction. This allows the heart muscle to relax after each contraction and prevents a permanent contraction (so-called tetany)!

Cells in the relative refractory and supernormal period are particularly susceptible to arrhythmias (e.g., ventricular fibrillation) when exposed to an inappropriately timed stimulus. During cardioversion, shock delivery needs to be synchronized with an R wave on ECG (indicating depolarization) and needs to be avoided during the relative and supernormal refractory periods (T waves, indicating repolarization)!

Regulation of cardiac activity

The heart can generate excitement on its own due to its pacemaker cells, but it must adapt its work to daily life requirements. Adaptation to short-term changes is provided by the Frank-Starling mechanism. Long-term changes in cardiac activity are regulated by the autonomic nervous system. The electrical activity of the heart can be recorded by electrocardiography. See ECG for an overview and interpretation of ECGs.

Frank-Starling mechanism

  • Definition: Compensatory mechanism of the heart that adjusts stroke volume according to the venous return in order to maintain cardiac output.
    • Length-tension relationship: larger volumes of blood in the ventricles stretch the cardiac muscle fibers and thereby lead to an increase in the force of contraction (↑ preload → ↑ end-diastolic length of cardiac muscle fibers → ↑ force of contraction (i.e., ↑ stroke volume).
  • Aim: Stroke volume of both ventricles should remain the same
  • Basic terms
    • Preload: The extent to which heart muscle fibers are stretched before the onset of systole. Depends on end-diastolic ventricular volume (EDV), which changes according to:
      • Venous constriction: ↑ venous tone → ↑ venous blood return to the heart → ↑ EDV → ↑ preload
      • Circulating blood volume: ↑ circulating blood volume → ↑ EDV → ↑ preload
    • Afterload: The force against which the ventricle contracts to eject blood during systole.
      • Afterload is primarily determined by the mean arterial pressure (MAP) in the aorta, which is influenced by total peripheral resistance.
      • Afterload → ↑ left ventricular pressure → ↑ left ventricular wall stress
      • According to LaPlace's law, ↑ left ventricular pressure → ↑ left ventricular wall stress
        • Left ventricular (LV) wall stress = (LV pressure × radius)/ 2×LV wall thickness

In chronic hypertension with a chronically increased afterload, the left ventricle undergoes hypertrophy to decrease left ventricular wall stress (↑ LV wall thickness → ↓ LV wall stress).

While an increase in preload leads to an increase in stroke volume, an increase in afterload leads to a decrease in stroke volume!

Autonomic innervation of the heart

The autonomic nervous system is able to regulate the heart action in the long term. Sympathetic fibers innervate both the atria and ventricles. Parasympathetic fibers only innervate the atria. The sympathetic nerve can therefore even alter the contraction force of the chambers (inotropy).

Sympathetic stimulation of the heart

Persistent epinephrine surges and long-lasting sympathetic activity can damage blood vessel endothelium, increase blood pressure, and raise the risk of heart attacks and strokes.

Parasympathetic stimulation of the heart

Initially, a diminished ejection fraction can be compensated by increased sympathetic tone, RAAS activation, ADH release, and the Frank-Starling mechanism. In the long term, however, these mechanisms increase cardiac work and lead to heart failure, which is why they are targeted by many drugs.

Factors that affect cardiac output

Factors that increase SV Factors that decrease SV
  • Increased venous return
    • During inspiration
    • When changing from upright to supine position
    • ↑ Skeletal muscle pump activity
Myocardial contractility
  • Increased myocardial contractility (↑ inotropy)
    • Sympathetic innervation (β1-receptor activation)
    • Catecholamines (e.g., epinephrine, norepinephrine, dopamine) through β1-receptor activation
    • High levels of blood and intracellular calcium
    • Thyroid hormones
    • Decreased extracellular Na+ (because subsequently, the activity of the Na+/Ca2+ exchanger will decrease)
    • Digitalis: inhibition of Na+/K+ pump → increased intracellular Na+ → decreased Na+/Ca2+ exchanger activity → increased intracellular Ca2+

Myocardial oxygen demand increases with an increase in the HR, myocardial contractility, afterload, and diameter of the ventricle.


Heart sounds and murmurs

Heart sounds are sounds that are generated during physiological heart action. Additional heart sounds may be heard in the context of pathological processes (e.g., stenosis of heart valves). These pathological heart sounds are referred to as heart murmurs. Both heart sounds and heart murmurs can be heard using a stethoscope at characteristic points on the chest. For more information, please see auscultatory locations, heart sounds, abnormal heart sounds, and heart murmurs in the learning card on cardiac examination.

Blood pressure regulation


To regulate organ perfusion, it is necessary to adapt circulatory parameters, such as pressure, volume status, and pH, with sensors and then process this information in a central regulatory center. The regulation center (in the medulla oblongata) acts on various effectors to control the blood flow in the short and long term.

Sensors of blood flow regulation

If the baroreceptors of the carotid sinus are too sensitive, even small stimuli such as turning the head or the pressure of a shirt collar can lead to excessive blood pressure reduction and even fainting. This is referred to as carotid sinus syndrome.

Central regulation of peripheral blood flow



  • Arteries: can change BP by increasing or decreasing resistance
  • Veins: can change circulating blood volume by adapting venous tone
  • Heart: can influence blood pressure by changing stroke volume and heart rate
Sympathetic stimulation Parasympathetic stimulation
Arteries Arterial constriction → ↑ peripheral vascular resistance Arterial vasodilation by means of releasing NO only in coronary arteries and vessels of the penis (erection)
Veins Venous constriction → ↑ preload→ ↑ stroke volume Venous dilatation → ↓ preload → ↓ stroke volume
Heart ↑ Contractility, ↑ heart rate Heart rate
  • Increased BP → ↑ firing frequency of baroreceptors (triggers baroreceptor reflex in brain stem) → ↑ parasympathetic stimulation and ↓ sympathetic innervation → vasodilatation → HR, SV, and BP decrease.


The renin-angiotensin-aldosterone system plays a key role in long-term blood pressure regulation and therefore is an ideal target when it comes to lowering a patient's blood pressure. While beta blockers decrease renin release by the kidneys, the conversion of angiotensin I to angiotensin II by angiotensin-converting enzyme (ACE) can be influenced by so-called ACE inhibitors (e.g., ramipril, enalapril). The effect of angiotensin II on receptors of target cells can be inhibited by AT1 receptor antagonists (e.g., candesartan, losartan).

In case of inadequate perfusion of organs and disturbed microcirculation (e.g., hypovolemic shock, cardiogenic shock, distributive shock), hypoperfusion is registered by baroreceptors and volume receptors, which leads to an increase in sympathetic tone. To maintain adequate brain and heart perfusion, the blood supply to the extremities (muscle, skin), the GI tract, and other internal organs is decreased (centralization of blood flow by autoregulatory mechanisms). Additionally, vasoconstriction of precapillary resistance vessels raises systemic vascular resistance and reduces hydrostatic pressure in capillaries, increasing reabsorption of interstitial fluids into vessels.

Autoregulation of organ perfusion

To keep blood flow within organs constant.

  • Myogenic mechanism
    • Site of action: almost all organs (especially kidney and brain)
    • Mechanism of action: ↑ BP (↑ transmural pressure) → stretch-activated ion channels open → cell depolarization and Ca2+ influx → smooth muscle contraction (vasoconstriction)

There is no myogenic autoregulation in the lungs! Here, an increase in perfusion and transmural pressure leads to vasodilation of pulmonary vessels to expand the gas exchange surface area.

  • Chemical mechanism
    • Site of action: arteries and arterioles
    • Mechanism of action: release of vasoactive substances
      • Nitric oxide (NO): produced in endothelium by NO-synthase from argininevasodilation
        • Triggered by:
          • ↑ BP
          • Activation of endothelial receptors by binding of vasoactive substances (e.g., serotonin, bradykinin) → increased release of NO
      • Other substances: kinin, histamine, serotonin, prostaglandins, thromboxane

Central regulation of organ perfusion

Cardiac blood pressures

Vascular resistance

Parallel resistance Series resistance
  • When an artery gives rise to two or more branches parallel to each other.
  • When an artery gives rise to two or more branches in-series.
  • 1/Rx = 1/R1 + 1/R2 + 1/R3, ...
  • Where Rx is the total resistance, and R1, R2, and R3 are three parallel vessels
  • Rx = R1 + R2 +R3, ...
  • Where Rx is the total resistance, and R1, R2, and R3 are three vessels in-series (e.g., artery, arteriole, capillary)
  • The total resistance of a network of parallel vessels is less than the resistance of any of the individual arteries.
  • As more vessels are added to a parallel network, the total resistance decreases.
  • Pressure is the same in each vessel in a parallel network.
  • The total resistance of a network of vessels in-series is more than the resistance of any of the individual arteries.
  • As more vessels are added to a parallel network, the total resistance increases.
  • Blood flow is the same in each vessel in a series network.

Organ perfusion

Blood flow varies greatly among tissues:

Organs % of cardiac output at rest % of cardiac output during exercise
Viscera (hepatic-splanchnic circulation) 24 1
Skeletal muscle 20 88
Kidneys 19 1
Brain 13 3

Other organs

10 1
Skin 8 2
Heart muscle 3 4

Autoregulation of different organs



Skeletal muscle

  • Accounts for the greatest proportion of body mass (45%), but it receives only 21% of blood flow at rest → blood flow can be increased (20–30 times) during exercise
  • Regulation:
    • At rest: sympathetic innervation
    • During exercise: local metabolic and chemical autoregulation: e.g., lactate, CO2, adenosine, K+, H+


  • Accounts for only 2% of body weight but receives 13% of cardiac output
  • Very constant total blood supply
  • Local blood flow depends on activities
  • Regulation: local metabolic autoregulation (CO2, pH → vasodilation) and myogenic mechanism


  • Level of skin blood flow is determined by how much is needed for the regulation of body temperature.
    • Regulated through capillaries and arteriovenous anastomoses
  • Regulation: mainly sympathetic innervation


  • Highest arteriovenous O2 difference of all organs (O2 extraction at rest ∼ 60–80%)
  • During exercise, there is little capacity to increase myocardial oxygen extraction (small coronary flow reserve)
  • Regulation: local metabolic autoregulation (adenosine and NO increase blood flow and oxygen delivery to the heart by vasodilatation of the coronary arteries)

Clinical significance

  • 1. Costanzo LS. Physiology Board review series. Lippincott Williams & Wilkins; 2014.
  • 2. Le T, Bhushan V,‎ Sochat M, Chavda Y, Zureick A. First Aid for the USMLE Step 1 2018. New York, NY: McGraw-Hill Medical; 2017.
  • Herold G. Internal Medicine. Cologne, Germany: Herold G; 2014.
  • Systrom DM, Lewis GD, Stoller JK, Hollingsworth H. Exercise Physiology. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. Last updated July 5, 2016. Accessed June 21, 2018.
last updated 12/03/2018
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